Stability and tolerability of high concentrations of intrathecal bupivacaine and opioid mixtures in chronic noncancer pain: an open-label pilot study.

OBJECTIVE: To evaluate the stability and tolerability of high concentrations of bupivacaine-opioid solutions when used by intrathecal infusion. DESIGN: Prospective, open label, pilot cohort study. SETTING: Outpatients at a University medical center. PATIENTS: Twelve patients with inadequate pain control already receiving intrathecal opioids and low dose bupivacaine. INTERVENTIONS: Increasing concentrations and doses of bupivacaine between 1 and 5% were prescribed to be added to a stable daily opioid dose. Drug infusate sampling and analysis using high performance liquid chromatography. OUTCOME MEASURES: Physical examination, assessment of pain and function between (0-60 days) using a linear visual analog scale, and the Oswestry Disability Index. RESULTS: Final daily doses of bupivacaine were 4-21.4 mg delivered at measured concentrations of 0.4-3.7%. Two patients experienced reversible motor weakness at 6 mg of bupivacaine/day. The in vitro and in vivo sampling of concentrations up to 3.7% of bupivacaine demonstrated that the stability for bupivacaine with morphine (1.2-3%) or hydromorphone (0.4-1%) was >96% of the manufactured concentration. There were no clinically significant changes in the visual analog pain scale or the Oswestry Disability Index. CONCLUSIONS: This in vivo study demonstrates excellent stability of high concentrations of intrathecal bupivacaine and opioid mixtures. No nonreversible neurological complications were identified in patients receiving daily doses of bupivacaine up to 21.4 mg. Tolerability was variable because of motor weakness. Given that all intrathecal local anesthetics may be neurotoxic, caution must be exercised if high concentrations and daily doses are to be delivered over prolonged periods.

Transfer of methylamphetamine and amphetamine into breast milk following recreational use of methylamphetamine.

AIMS: To investigate the transfer of amphetamines into breast milk following their recreational use and estimate drug exposure for the breastfed infant. METHODS: Two breastfeeding mothers who were occasional recreational users of intravenous amphetamines were studied. A urine sample was collected 4 h after dose, and milk samples were collected over 24 h. Drug in urine was qualitatively identified by gas chromatography-mass spectrometry and quantification in milk was by high-performance liquid chromatography. Absolute infant dose via milk was estimated. RESULTS: The urines contained predominantly methylamphetamine together with smaller amounts of amphetamine. In the 24 h after dose, average concentrations in milk were 111 microg l(-1) and 281 microg l(-1) for methylamphetamine and 4 microg l(-1) and 15 microg l(-1) for amphetamine in cases 1 and 2, respectively. Absolute infant doses for methylamphetamine plus amphetamine (as methylamphetamine equivalents) were 17.5 microg kg(-1) day(-1) and 44.7 microg kg(-1) day(-1), respectively, for cases 1 and 2. CONCLUSION: These limited data suggest that breastfeeding should be withheld for 48 h after recreational amphetamine use.

Investigation of target plasma concentration-effect relationships for olanzapine in schizophrenia.

Olanzapine is an atypical antipsychotic effective in the treatment of schizophrenia. The present study has examined the potential use of target concentration monitoring of olanzapine in plasma as a marker of clinical response and an aid in patient management. Fifty-three patients (mean age 32 years; 40 M, 13 F) with a DSM-IVR diagnosis of schizophrenia completed a 6-week trial of oral olanzapine. Participants received once-daily olanzapine, and their psychotic symptoms were measured with the PANSS (Positive and Negative Symptom Scale) on admission and again after 6 weeks. Responders were classified as having a >/=20% decrease in PANSS scores. Plasma olanzapine was quantified by high-performance liquid chromatography. Receiver operator characteristic (ROC) curve analysis was used to identify a break point in plasma olanzapine that might serve as a surrogate for PANSS classification, and the two methods were compared using the McNemar chi2 test. After 6 weeks the median olanzapine dose was 15 mg/d (range 5-30 mg/d), and the mean plasma olanzapine was 32 micrograms/L at a mean of 13.5 hours after dose. With the PANSS (total), there were 42 responders and 11 nonresponders. ROC curve analysis for total PANSS identified a break point at 23 micrograms/L plasma olanzapine, with the proportions of responders and nonresponders identified by PANSS and the plasma break point being similar. Similar break points were found for the positive, negative, and global PANSS subscores. Nevertheless, these relationships were very modest, and at best the target plasma olanzapine concentration identified only 20% more responders than nonresponders. We suggest that plasma olanzapine monitoring can be used for dose-response optimization, but only to complement the normal clinical evaluation process.

Optimizing the hydrolysis of codeine and morphine glucuronides in urine.

Quality assurance data show that there is very significant inter-laboratory variation of the quantitation of codeine, especially in patient samples. The authors have examined hydrolysis procedures for codeine glucuronide (C6G) and morphine-3- and -6-glucuronides (M3G, M6G) because these are often present together in urine samples. Comparisons of hydrolysis using two different sources of beta-glucuronidases and various concentrations of hydrochloric acid were made. Samples were concentrated using solid phase extraction, derivatized and quantified by selective ion monitoring using gas chromatography-mass spectrometry (GC-MS). and beta-glucuronidase efficiently hydrolyzed M3G (90-95%), while hydrolysis of M6G was lower (60-85%) and that of C6G was very poor (45-58%). These findings were confirmed on examination of urine samples containing codeine and morphine from subjects who had taken codeine, morphine, or heroin. Erratic inter-laboratory quality assurance results for codeine are most probably a result of incomplete C6G hydrolysis. The authors' optimized hydrolysis method using 50% HCl for 1.5 hours at 120 degrees C gave reproducible results that approached the spiked concentration.

Determination of olanzapine in plasma by high-performance liquid chromatography using ultraviolet absorbance detection.

A rapid method for the determination of olanzapine in plasma using high-performance liquid chromatography with ultra violet detection is described. Olanzapine was extracted from plasma with a mixture of hexane/dichloromethane (85:15), and then back extracted into phosphate buffer pH 2.8. Separation was achieved on a RP Select B C(18) column and commonly administered drugs did not interfere with the assay. The limit of quantitation was 1.5 microg/l and the inter-day and intra-day relative standard deviations were less than 10%. Olanzapine was shown to be stable in plasma for up to 7 days when stored at 4 degrees C. Moreover, the addition of ascorbic acid was not necessary for the achievement of chemical stability during storage, or during the assay procedure. The method has been used to measure olanzapine concentrations in patients treated with various doses of the drug varying from 5 to 40 mg/day.